Objectives

To evaluate the impact of neutralizing monoclonal antibody (mAb) treatment and to determine whether the selective pressure of mAbs could facilitate the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with spike protein mutations that might attenuate mAb effectiveness.

Patients and methods

We evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single-molecule real-time sequencing. The mAbs used were: Bamlanivimab alone (four patients), Bamlanivimab/Etesevimab (23 patients) and Casirivimab/Imdevimab (five patients).

Results

The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log₁₀ copies/mL before administration to 4.3 log₁₀ copies/mL 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAb activity-reducing spike mutations. Two patients harboured SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harboured a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in three of five patients.

Conclusion

Two-mAb therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread should be reinforced.

中文翻译：

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中和单克隆抗体治疗对 SARS-CoV-2 鼻咽负荷和准种的影响

目标

评估中和单克隆抗体 (mAb) 治疗的影响，并确定 mAb 的选择压力是否会促进严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 变异体的增殖，这些变异体具有可能减弱 mAb 有效性的刺突蛋白突变。

患者和方法

我们使用单分子实时测序评估了 mAb 对 mAb 治疗患者的鼻咽 (NP) 病毒载量和病毒准种的影响。使用的 mAb 是：单独使用 Bamlanivimab（4 名患者）、Bamlanivimab/Etesevimab（23 名患者）和 Casirivimab/Imdevimab（5 名患者）。

结果

接受 mAb 治疗的患者的 NP SARS-CoV-2 病毒载量从给药前的8.2 log ₁₀拷贝/mL 降至给药后 7 天的4.3 log ₁₀拷贝/mL。发现五名接受 Bamlanivimab/Etesevimab 的免疫功能低下患者具有降低 mAb 活性的尖峰突变。两名患者在给药 7 天后携带具有 Q493R 尖峰突变的 SARS-CoV-2 变体，第三名患者在给药后 14 天也如此。第四名患者在治疗后 7 天携带 Q493K 尖峰突变的变异，第五名患者在第 21 天携带 E484K 尖峰突变的变异。尖峰突变的出现伴随着 NP 病毒载量的稳定或反弹五名患者中的三名。

结论

两种 mAb 疗法可以推动在免疫功能低下的患者中选择抗性 SARS-CoV-2 变体。应密切监测接受 mAb 的患者，并应加强限制病毒传播的措施。